Analgesic method

ABSTRACT

Disclosed herein are analgesic copper coordination compounds and a process for using them in the treatment of analgesia in animal bodies. The copper coordination compounds utilized are the reaction products of copper salts with: 
     1. carboxylic acids or their alkaline earth salts; 
     2. aromatic carboxylic acids or their alkaline earth salts; 
     3. heterocyclic carboxylic acids or their alkaline earth salts; 
     4. amino acids or their alkaline earth salts; 
     5. anthranilic acids or their alkaline earth salts; 
     6. salicylic acids or their alkaline earth salts; 
     7. acetylsalicylates or their alkaline earth salts; 
     8. arylacetic acids or their alkaline earth salts; 
     9. disubstituted aminodithiocarbamates, and mixtures of any of the above. 
     The process disclosed comprises administering to animals, orally or parenterally, in controlled dosages, the aforementioned copper coordination compounds.

RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 426,456filed Oct. 20, 1989, now U.S. Pat. No. 4,999,347 which in turn was acontinuation of U.S. application Ser. No. 901,191 filed Aug. 28, 1986,now abandoned.

BACKGROUND OF THE INVENTION

Morphine, while a strong, analgesic, is of course very addictive andconsequently its use must be strictly controlled and monitored. Whilethere are various antiinflammatory compounds that are mild analgesicsthat are not addictive, their use is limited because of their low orderof weak activity. Some, to, are antiinflammatory but their use islimited because they are ulcergenic.

It has therefore been a principal objective of my invention to providean analgesic treatment utilizing more potent compounds. It has also beenan objective to provide such a treatment with compounds whose analgesicactivity approach and equal or exceed that of morphine.

SUMMARY OF THE INVENTION

It has been quite unexpectedly discovered that copper coordinationcompounds produced by reacting alkaline earth salts of the followingclasses of organic compounds with loosely bonded forms of copper toproduce products which when used in accordance with the followingprocesses, exhibit excellent analgesic activity in animals, i.e., awarm-blooded animal or mammalian subject:

1. carboxylic acids or their alkaline earth salts;

2. aromatic carboxylic acids or their alkaline earth salts;

3. heterocyclic carboxylic acids or their alkaline earth salts;

4. amino acids or their alkaline earth salts;

5. anthranilic acids or their alkaline earth salts;

6. salicylic acids or their alkaline earth salts;

7. acetylsalicylates or their alkaline earth salts;

8. arylacetic acids or their alkaline earth salts;

9. disubstituted aminodithiocarbamates, and mixtures of any of theabove.

More particularly, the following classes of organic compounds and thespecified copper coordination compounds produced therefrom have provento be especially useful:

a. Salicylic Acids: Cu(II) (salicylate)₂, Cu(II)(3,5-diisopropylsalicylate)₂

b. Acetylsalicylic Acids (an aromatic carboxylic acid): Cu(II)₂(Acetylsalicylate)₄

c. Anthranilic Acids: Cu(II) (anthranilate)₂

d. Nicotinic Acids: Cu(II)₂ {2-[3-(trifluoromethyl)phenyl]aminonicotinate}₄

e. Arylacetic Acids: Cu(II)₂[1-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylacetate]₄

f. Amino Acids: Cu(II) (alaninate)₂, Cu(II) (cystinate)₂, and Cu(II)(glycinate)₂

g. Carboxylic Acids: Cu(II)₂ (acetate)₄

h. Disubstitutedaminodithiocarbamates: Cu(II) (diethyldithiocarbamate)₂

It has been empirically determined that the copper coordinationcompounds disclosed herein not only demonstrate excellentanti-inflammatory activity and anti-ulcer activity but they are alsoexcellent analgesics. Some of the compounds of the present inventionhave an activity that approaches that of morphine.

The compounds can be administered orally or parenterally. The coppercoordination compounds, being relatively insoluble in water, areadministered by suspending them in saline solution to which a suitablesuspending agent has been added.

In treating pain by injection test animals with the copper coordinationcompound so prepared it has been found that excellent results, in thetest models hereinafter described, may be obtained if the dosagesadministered comprise about 0.1-500 mg. per kilogram of body weight.

In using the compounds of the present invention it has been found thatexcellent results are obtained if the dosages administered compriseabout 0.5 to 400 mg. per kilogram of body weight.

DETAILED DESCRIPTION OF THE INVENTION

For the purpose of more fully understanding the present invention, acopper coordination compound is intended to mean a compound whosemolecular structure contains one or more copper atoms bonded to one ormore atoms of one or more molecules or ions by coordinate covalentbonds.

The copper coordination compounds of the present invention are preparedby reacting copper salts, preferably cupric chloride or cupric acetatewith a member of the following classes of organic compounds;

1. carboxylic acids or their alkaline earth salts;

2. aromatic carboxylic acids or their alkaline earth salts;

3. heterocyclic carboxylic acids or their alkaline earth salts;

4. amino acids or their alkaline earth salts;

5. anthranilic acids or their alkaline earth salts;

6. salicylic acids or their alkaline earth salts;

7. acetylsalicylates or their alkaline earth salts;

8. arylacetic acids or their alkaline earth salts;

9. disubstituted aminodithiocarbamates, and mixtures of any of theabove.

More specifically, it has been found that suitable compounds may beproduced by reacting cupric chloride with the sodium salts of L & Dtryptophan, anthranilic acid, 3,5-diisopropylsalicylic acid,acetylsacicylic acid, hydrocortisone-21-phosphate,dexamethasone-21-phosphate, salicylic acid, 3-p-chlorophenyl-3, 4, 5,6,-tetrahydro-β-carboline5-carboxylic acid, 3, 4, 5,6-tetra-hydro-β-carboline-5-carboxylic acid, and1-(p-chlorobenzoyl)-5-methoxy-2-methylinodole-3-acetic acid; by reactingcupric chloride with 1-phenyl-5-aminotetrazole, ε-aminocaproic acid,pyridine, a mixture of D and L-tryptophan, morpholine, and histamine; byreacting cupric chloride with the ammonium salt ofhydrocortisone-21-hemisuccinic acid; by reacting cupric acetate with thesodium salts of 2[3(trifluoro-methyl)phenyl] aminonicotinic acid(sometimes referred to hereinafter as niflumic acid),1-carboxyisoquinoline, phenylcinchoninic acid,hydrocortisone-21-phosphate, and4-n-butyl-1,2-diphenyl-3,5-pyrazolidinedione; by reacting cupric acetatewith the ammonium salt of nicotinic acid; by reacting cupric acetatewith D-pencillamine, 1-phenyl-5-aminotetrazole, D or L-aspartic acid,L-lysine, 2-carboxyindole; and by reacting cupric acetate with thepotassium salt of 17-hydroxy-3-oxo-17α-pregn-4,6,-diene-21 carboxylicacid.

It is preferable to produce copper coordination solvates rather thananhydrous compounds as will be more fully appreciated by the followingdescription. The compounds may be solvated with a lower alcohol(methanol or ethanol), acetone, pyridine, water or dimethyl sulfoxide.

Following is a more detailed description of how the copper coordinationcompounds of the present invention may be prepared. Not all have beenempirically determined.

EXAMPLE 1 Bis-L-tryptophanato(O,N)copper(II), [Cu(II)(L-tryptophan)₂ ]

L-tryptophan (5.0 g, 0.025 mol) was dissolved in 100 ml of H₂ O with asolution of NaOH (50%), filtered and back titrated if necessary with asolution of HCl (10%) until indicator paper showed the solution to beweakly basic. This solution was then dropped into 100 ml of H₂ Ocontaining CuCl₂ dihydrate (3.3 g, 0.021 mol). After stirring for aboutone hour a precipitate formed and was collected by filtration. This blueprecipitate was washed with H₂ O and diethylether, dried at 100° and 15mm Hg overnight and weighed (4.7 g, 82% yield). A sample of thismaterial on heating turned brown at 240° C. and finally decomposed at260° C. Analysis Calcd. for C₂₂ H₂₂ N₄ O₄ Cu: C, 56.22; H, 4.72; N,11.92. Found: C, 56.07; H, 4.89 and N, 12.16.

EXAMPLE 2 Bis-D-tryptophanato(O,N)copper(II)[Cu(II)(D-tryptophan)₂ ]

This coordination compound was prepared as described for the L isomer(example 1) using 5.0 g, 0.021 mol of D-tryptophan. After collecting theprecipitate by filtration, washing with H₂ O, diethylether and acetone(250 ml), the precipitate was dried overnight at 100° and 15 mm Hg andweighed (4.3 g, 75% yield). A sample of this material decomposed slowlyon heating to 269° C. Analysis Calcd. for C₂₂ H₂₂ N₄ O₄ Cu: C, 56.22; H,4.72; N, 11.92. Found: C, 56.10, H, 4.72 and N, 12.00.

EXAMPLE 3 Bisanthranilato(O,N)copper(II),[Cu(II)(anthranilate)₂ ]

The sodium salt of anthranilic acid (5 g 0.04 mol) was prepared asdescribed in example 1 in 150 ml of H₂ O with 50% NaOH. This solutionwas dropped into 300 ml of a stirred aqueous solution of CuCl₂ dihydrate(2.5 g, 0.016 mol). The precipitate which formed was removed byfiltration and washed with H₂ O and diethylether (5×50 ml). After dryingovernight @120° C. and 15 mm Hg the material weighed 6.1 g, 99% yield. Asample of this greenish-blue material decomposed on heating to 240° C.and continued to decompose on heating to 290° C. Analysis Calcd. for C₁₄H₆ N₂ O₄ Cu: C, 50.07; H, 3.60; N, 8.35. Found: C, 50.07; H, 3.77; N,8.42.

EXAMPLE 4 Bis(3,5-diisopropylsalicylato(O,O)copper(II)[Cu(II)(3,5-dips)₂ ]

A solution of the sodium salt of 3,5 -diisopropylsalicylic acid (5 g,0.023 mol) was prepared as described in example 1 and added to 300 ml ofa stirred aqueous solution of CuCl₂ dihydrate (1.59 g, 0.0336 mol). Abrown precipitate formed which when recrystallized from ether gave greencrystals. These crystals were filtered and dried at 125° C. and 15 mm Hgfor three hours. The resulting brown crystalline material melted withdecomposition over the range of 142°-144° C. Analysis Calcd. for C₂₆ H₃₄O₃ Cu: C, 61.70; H, 6.77. Found: C, 61.49; H, 6.83.

EXAMPLE 5 Tetra(μ-acetylsalicylato)biscopper(II),[Cu(II)₂ (aspirinate)₄]

The sodium salt of acetylsalicylic acid was prepared by dissolvingacetylsalicylic acid (30 g, 0.165 mol) in 200 ml of H₂ O at 0° C. with50% NaOH so that the pH did not go above 11.0 and rarely reached 11.0.This was done over a period of 45 to 60 minutes. The final pH of thesolution was about 8.7. The CuCl₂ solution prepared by adding 56.5 g,0.330 mol of CuCl₂ dihydrate to 500 ml of water, was added to a stirredsolution of sodium acetylsalicylate during a period of 10 to 15 minutes.Following the completion of this addition the blue precipitate wascollected by filtration; washed with H₂ O (500 ml×2), acetone (400 ml×2)and diethylether (300 ml) and left to dry on a filter funnel attached toa water aspirator. After two days the powder was dried at 50° C. for 6-7hours and weighed (31.3 g, 90.6% yield). Analysis calculated for C₃₆ H₂₈O₁₆ Cu₂ : C, 51.25; H, 3.35; Found: C, 51.20; H, 3.51.

EXAMPLE 6 [2[3(trifluoromethyl)phenyl]aminonicotinato]_(2n) -(aqua)_(n)-copper(II)_(n),[Cu(II)_(n) (niflumate)_(2n) (H₂ O)_(n) 9

The sodium salt of 2[3(trifluoromethyl)pheynl] aminonicotinic acid (20g, 0.0708 mol) was prepared as described in example 1. The solution ofthis salt was then added to about 300 ml of a saturated, stirredsolution of cupric acetate monohydrate. The resultant greenishprecipitate was collected by filtration and dissolved in 200 ml ofdiethylether. The ether solution was then dropped into about 4 liters ofboiling skellysolve A. The resultant precipitate was collected from thehot solution by filtration, dried at 125° C. for three hours at 15 mm Hgand weighed (16 g, 70% yield). A sample of this material melted withdecomposition over the range of 201° to 208° C. Analysis Calcd. for C₅₂H₃₆ O₁₀ N₈ F₁₂ Cu: C, 48.49; H, 2.82; N, 8.70. Found: C, 48.53; H, 2.66;N, 8.91.

EXAMPLE 7 D-penicillaminato-(aqua)₁.5 -copper(I),[Cu(I)_(n) (D-pen)_(n)(H₂ O)₁.5n ]

D-penicillamine (5 g, 0.0335 mol) was dissolved in 50 ml of water. Thesolid cupric acetate monohydrate (6.68 g, 0.017 mol) was then added tothe solution at such a rate so as to not exceed its rate of solution.Upon the completion of this addition the solution was dark gray. About50-100 ml of H₂ O was then added and the mixture left to stir for about30 minutes. The resultant gray precipitate was collected by filtrationleaving a blue filtrate (125 ml). This blue filtrate was subsequentlydiluted with about 375 ml of acetone and set aside for use in example 8.The air-dried gray powder weighed 4.3 g, 54.0% yield. A sample of thismaterial decomposed over the range of 155°-157° C. Analysis Calcd. forC₅ H₉ SNO₃.5 Cu: C, 25.26; H, 5.10, N, 5.89. Found: C, 25.32; H, 5.03;N, 5.47.

EXAMPLE 8 (D-penicillaminato)_(2n) -(aqua)_(2n) -copper(II),[Cu(II))_(n)(D-pen)_(2n) (H₂ O)_(2n) ]

On standing, the acetone diluted blue filtrate described in thepreparation of Example 7 gave a gray precipitate which was collected byfiltration and this filtrate also set aside. The gray solid was washedwith 60 ml of water and the remaining light tan solid washed with 60 mlof acetone air dried and weighed (1.15 g, 17.4% yield). A sample of thissolid melted with decomposition over the range of 155° to 157° C.Analysis Calcd. for C₁₀ H₂₄ O₆ S₂ N₂ Cu: C, 30.33; H, 6.11; N, 7.08.Found: C, 30.42; H, 6.49; N, 6.72.

EXAMPLE 9 (D-pencillamine disulfide)_(n) -(aqua)_(3n) copper(II)_(n),[Cu(II)_(n) (D-pen disulfide)_(n) (H₂ O)_(3n) 9

The acetone-water filtrate obtained after removing example 8 from theblue acetone filtrate, described above, was concentrated to about 100 mland diluted with 400 ml of acetone. A blue precipitate (1.3 g, 9.4%yield) was obtained following filtration, washing with acetone and airdrying. A sample of this material decomposed over the range of 157° to158° C. After drying twice at 73° and 15 mm Hg overnight a sample ofthis material decomposed over the range of 173° to 175° C. AnalysisCalcd. for C₁₀ H₂₄ N₂ S₂ O₇ Cu: C, 29.15; H, 5.87; N, 6.80. Found: C,29.43; H, 5.76; N, 6.36.

EXAMPLE 10 (Acetato)_(2n) -(1-phenyl-5-aminotetrazolato)_(n)-copper(II)_(n) [Cu(II)_(n) (pat)_(n) (acetate)_(2n) ]

Five grams of cupric acetate monohydrate (0.012 mol) was dissolved in 20ml of H₂ O. This solution was diluted with 100 ml of methanol. 5 g (0.31mol) of 1-phenyl-5-aminotetrazole was added to obtain a blue gel. Thisgel was filtered and the resulting blue flakes were washed with about400 ml of methanol until the washings were no longer blue. The filtratewas then concentrated to about 150 ml and stored for about one week inthe refrigerator. A precipitate formed and was removed by filtration.This green crystalline solid was air dried and weighed (3.8 g, 17.9%yield). A sample of this solid decomposed over the range of 186°-189° C.Analysis Calcd. for C₂₂ H₂₆ N₁₀ O₈ Cu₂ : C, 38.54; H, 3.82; N, 20.43.Found: C, 38.42; H, 3.94; N, 20.92.

EXAMPLE 11 (1-phenyl-5-aminotetrazolato)_(2n) -(chloride)_(2n) -copper(II)_(n),[Cu(II)_(n) (pat)_(2n) (HCl)_(2n) ]

Five grams (0.012 mol) of 1-phenyl-5-aminotetrazole was dissolved in 30ml of methanol, then 5 g (0.029 mol) of CuCl₂ dihydrate dissolved in 25ml of methanol was added to the stirred solution of tetrazole. Theresulting solution was filtered and set aside. Three subsequent crops ofa green solid were obtained following filtration and concentration ofthe filtrate. The combination of these were air dried and weighed (5 g,17.7% yield). A sample of this material decomposed on heating over therange of 184° to 185° C. Analysis Calcd. for C₁₄ H₁₄ N₁₀ CuCl₂ : C,36.81; H, 3.09; N, 30.67. Found: C, 36.65; H, 3.17; N, 31.03.

EXAMPLE 12 (D-Aspartato)_(n) (aqua)₃.5n -copper(II)_(n),[Cu(II)_(n)(D-aspartate)_(n) (H₂ O)₃.5n ]

This material is made in a manner similar to the preparation of example1 using D-aspartic acid in place of L-tryptophan. Analysis calculatedfor C₄ H₁₂ N O₇.5 Cu: C, 18.69; H, 4.66. Found: C, 18.55; H, 4.92.

EXAMPLE 13 (L-Aspartato)_(n) -(aqua)₃.5n -copper(II)_(n),[Cu(II)_(n)(L-aspartate)_(n) (H₂ O)₃.5n ]

This material is made in a manner similar to the preparation of example1 using L-aspartic acid in place of L-tryptophan. Analysis calculatedfor C₄ H₁₂ N O₇.5 Cu: C, 18.69; H, 4.66. Found: C, 18.41; H, 4.73.

EXAMPLE 14 (L-Lysino)_(n) -(chloro)_(2n) -(aqua)_(n)-copper(II)_(n),[Cu(II)_(n), (L-lysinate)_(n) (Cl)_(2n) (H₂ O)_(n) ]

This material is made in a manner similar to example 1 using L-lysine inplace of L-tryptophan. A sample of this material decomposed on heatingover the range of 169° to 170° C. Analysis calculated for C₆ H₁₆ N₂ O₃CuCl₂ : C, 24.10; H, 5.40; Cl, 23.70; N, 9.38. Found: C, 24.54; H, 5.07;Cl, 24.00; N, 9.36.

EXAMPLE 15 (L-Lysino)_(2n) -(chloro)_(2n) -(aqua)_(n)-copper(II)_(n),[Cu(II)_(n) (L-lysinate)_(2n) (Cl)_(2n) (H₂ O)_(n) ]

This material is made in a manner similar to example 1 using L-lysine inplace of L-tryptophan. A sample of this compound decomposed on heatingup to and over the range 210° to 214° C. Analysis calculated for C₁₂ H₃₂N₄ O₅ CuCl₂ : C, 32.40; H, 6.80; Cl, 12.60. Found: C, 32.56; H, 7.04;Cl, 12.24.

EXAMPLE 16 Bis(D,L-tryptophanato(O,N)copper(II),[Cu(II)(D,L-tryptophan)₂]

This coordination compound was prepared and isolated as described inexample 1 using a mixture of D and L-tryptophan in place ofL-tryptophan. Analysis Calcd. for C₂₂ H₂₂ N₄ O₄ Cu: C, 56.22; H, 4.72.Found: C, 55.58; H, 4.87.

EXAMPLE 17 (ε-aminocaproato)_(n) -(chloro)₁.5n -(methanol)₀.5n -copper(II)_(n),[Cu(II)_(n) (ε-aminocaproate)_(n) (Cl)₁.5n (CH₃ OH)₀.5n ]

This coordination compound was prepared by stirring a suspension of 10 g(0.08 mol) of ε-aminocaproic acid in 200 ml of methanol and slowlyadding 10 g (0.065 mol) of solid cupric chloride dihydrate. Theresultant green precipitate was collected by filtration washed withmethanol, dried at 25° C. and 15 mm Hg overnight, and weighed (10.5 g,51% yield). A sample of this material decomposed over the range of 157°to 158° C. Analysis Calcd. for C₇ H₁₅.5 O₂.5 CuCl₁.5 C, 29.53; H, 5.91;Cl, 20.11. Found: C, 29.97; H, 6.06; Cl, 20.36.

EXAMPLE 18 (ε-aminocaproato)_(n) -(chloro)_(2n) -(aqua)₀.5n-copper(II)_(n), [Cu(II)_(n) (ε-aminocaproate)_(n) (Cl)_(2n) (H₂ O)₀.5n]

This coordination compound was obtained from the filtrate described inexample 17.

Following concentration of the filtrate and methanol washings to about100 ml of bluish-green precipitate formed. This precipitate wascollected by filtration dried at 25° C. at 15 mm Hg and weighed (4.6 g,21% yield). A sample of this material decomposed on heating over therange of 193° to 194° C. Analysis Calcd. for C₆ H₁₄ NO₂.5 Cl₂ Cu: C,26.24; H, 5.14; Cl, 25.82. Found: C, 26.29; H, 5.28; Cl, 25.39.

EXAMPLE 19 tetra(μ-acetato)bis(monopyridino)copper(II),[Cu(II)_(n)(pyridine)_(n) (acetate)_(2n) ]

This coordination compound was prepared by adding 10 g (0.025 mol) ofcupric acetate monohydrate to 70 ml of pyridine and the mixture heatedwhile stirring at 100° C. The hot suspension was filtered and theresulting precipitate collected by filtration and washed with 200 to 300ml of diethylether. A sample of this green solid decomposed on heatingover the range of 214° to 216° C. When the ether-pyridine filtratecooled a second precipitate, which was bluish, was obtained. Removal byfiltration and washing with ether gave a second crop of the greenmaterial in the filtrate. This green solid had a decomposition range of216° to 218° C. A mixture decomposition range of 216° to 218° C. wasobserved for a sample of the combination of the two green solids. Totalyield was 12 g, 92%. Analysis Calcd. for C₁₈ H₂₂ N₂ O₈ Cu₂ : C, 41.46;H, 4.25; N, 5.37. Found: C, 41.87; H, 4.54; N, 5.23.

EXAMPLE 20 Bispyridinobishchlorocopper(II),[Cu(II)(pyridine)₂ (Cl)₂ ]

This composition was prepared by dissolving 9.42 g (0.062 mol) of CuCl₂dihydrate in 95% ethanol and adding 15 g (0.19 mol) of pyridine slowlyto the stirred solution. The resultant blue precipitate was removed byfiltration, washed with 95% ethanol (200 ml), dried at about 50° C. for24 hours and weighed (19.8 g, 35.6% yield). A sample of this materialdecomposed over the range of 225° to 275° C. Analysis Calcd. for C₁₀ H₁₀N₂ CuCl₂ : C, 41.32; H, 3.44. Found: C, 41.25; H, 3.52.

EXAMPLE 21 Bismorpholoniumtetrachlorocopper(II),[Cu(II) (morpholine)₂(Cl)₂ (HCL)₂ ]

This coordination compound was prepared according to the publishedprocedure of W. H. C. Rueggeberg, G. N. Jarman and R. B. Wearn,J.A.C.S., 69, 1222 (1947) incorporated by reference herein. Startingwith 14.5 g (0.167 mol) of morpholine the coordination compound wasobtained in 41% yield. A sample of this green crystalline melted withdecomposition over the range of 167°-170° C. Analysis Calcd. for C₈ H₂₀N₂ O₂ CuCl₄ : C, 25.17; H, 5.28; N, 7.34. Found: C, 25.17; H, 5.41; N,7.21.

EXAMPLE 22 (Histamino)_(n) -(chloro)_(2n) -(hydrochloro)_(2n)-copper(II)_(n), [Cu(II)_(n) (histamine)_(n) (Cl)_(2n) (HCl)_(2n) ]

This coordination compound was prepared by mixing 5 g (0.048 mol) ofcupric chloride dihydrate in 200 l of methanol and concentrating to 135ml. On standing a tan solid precipitated. This was removed by filtrationand the filtrate concentrated to 80 ml. Upon addition of 40 ml ofdiethylether to this concentrate a light green solid precipitated. Afterremoval by filtration and air drying this material was weighed (4.0 g,23% yield). A sample decomposed over the range of 185° to 189° C. withsoftening at 182° C. Analysis Calcd. for C₅ H₁₀ N₃ Cl₄ Cu: C, 18.91; H,3.17; N, 13.24. Found: C, 18.90, H, 3.30; N, 13.30.

EXAMPLE 23 (Sodium)₄ -(salicylato)₄ -copper(II)₂,[Cu(II)₂ (salicylate)₄(Na)₄ ]

This material was prepared from the material obtained in example 24 withthe addition of sodium ethoxide in suitable solvant. Analysis calculatedfor C₂₈ H₁₆ O₁₂ Cu₂ Na₄ were found to be within ±0.4% of the theoreticalvalues.

EXAMPLE 24 (Salicylato)_(2n) -(aqua)_(4n) -copper(II)_(n),[Cu(II)(Salicylate)₂ (H₂ O)₄ ]

This material may be prepared as described in example 1 using salicylicacid in place of L-tryptophan. Analysis calculated for C₁₄ H₁₈ O₁₀ Cu:C, 41.03; H, 4.43. Found: C, 41.24; H, 4.52.

EXAMPLE 25 (Pyridine-3-carboxylato)_(2n) -(aqua)₁.5n -copper(II),[Cu(II)_(2n) (nicotinate)_(4n) (H₂ O)_(3n) ]

This coordination compound was prepared by dissolving 10 g (0.08 mol)nicotinic acid in 100 ml of water with concentrated NH₄ OH so that thefinal pH was 7.0. A cupric chloride solution, prepared by dissolving21.6 g (0.14 mol) of cupric chloride dihydrate in 200 ml of water, wasstirred while the ammonium salt of nicotinic acid was added dropwise.The blue precipitate was collected by filtration, washed with 500 ml ofwater and air dried. The resulting material was dried at 80° C. andweighed (10.7 g, 80% yield). A sample of this material decomposed onheating up to and through the range of 265° to 266° C. Analysis Calcd.for C₂₄ H₂₂ O₁₁ N₄ Cu₂ : C, 43.05; H, 3.31; N, 8.37. Found: C, 43.25; H,3.00; N, 8.12.

EXAMPLE 26 (Isoquinoline-1-carboxylato)_(2n) -copper(II)_(n),[Cu(II)_(n)(1-carboxyisoquinoline)_(2n) ]

The copper coordination compound of 1-carboxyisoquinoline (5 g 0.029mol) was prepared by adding to its solution of the sodium salt, preparedas in example 1 in 200 ml of water using 1-carboxyisoquinoline in placeof L-tryptophan, 60 ml of a saturated aqueous solution of cupric acetatemonohydrate. The resultant purple precipitate was collected byfiltration, washed with 500 ml of water and dried overnight at 100° C.and 15 mm Hg. A sample of this material (4.0 g, 70.2% yield) decomposedover the range of 295° to 296° C. Analysis Calcd. for C₂₀ H₁₂ N₂ O₄ Cu:C, 58.84; H, 2.97; N, 6.87. Found: C, 58.49; H, 3.14; N, 6.79.

EXAMPLE 27 (2-Phenyl-4-isoquinoline-carboxylato)_(2n) -(aqua)_(2n)-copper(II)_(n),[Cu(II)_(n) (2-phenyl-4-carboxyisoquinoline)_(2n) (H₂O)_(2n) ]

This coordination compound was synthesized from the sodium salt ofphenylcinchoninic acid (25 g, 0.15 mol), which was prepared as describedin example 1 using "2-phenyl-4-isoquinolinecarboxylic acid" in place ofL-tryptophan in 550 ml of water. The solution of the sodium salt wasdropped into a stirred solution of cupric chloride dihydrate (14.2 g,0.09 mol). The resulting green precipitate was collected by filtration,washed with methanol, water and then air dried and weighed (29.5 g, 67%yield). A sample of this material decomposed on heating over the rangeof 228° to 229° C. Analysis Calcd. for C₆₄ H₄₈ N₄ O₁₂ Cu₂ : C, 64.48; H,4.06; N, 4.70. Found: C, 64.55; H, 3.80; N, 4.61.

EXAMPLE 28 (Indole-2-carboxylato)_(3n) -(acetato)_(n) -(aqua)₀.5n,[Cu(II)_(n) (2-carboxyindole)_(3n) (acetate)_(n) (H₂ O)₀.5n ]

This copper coordination compound was prepared from the parent acid2-carboxyindole (4.5 g, 0.028 mol) as in example 1, using cupricacetate. The green precipitate was collected by filtration, air driedfor several days, suspended in boiling methanol and again collected byfiltration. It was then dried at 100° C. and 15 mm Hg overnight and at125° and 15 mm Hg for 3 hours. A sample of this material (3.0 g, 23.3%yield) decomposed over the range of 249°-255° C. Analysis Calcd. for C₂₉H₂₂ N₃ O₉ Cu: C, 56.91; H, 3.59; N, 6.86. Found: C, 56.87; H, 4.03; N,6.62.

EXAMPLE 29 (Indole-2-carboxylato)_(3n) -(acetato)_(n) -(aqua)₃.5n,[Cu(II)_(n) (2-carboxyindole)_(3n) (acetate)_(n) (H₂ O)₀.5n ]

This material was prepared as described in example 1 using 2-carboxyindole in place of L-tryptophan and dried at 100° C. and 15 mmHg over the weekend. A sample of this material did not melt but did turnbrown, as did the material in example 28, on heating to 260°. AnalysisCalcd. for C₂₉ H₂₈ N₃ O₁₂ Cu: C, 52.29; H, 4.20; N, 6.30. Found: C,51.85; H, 3.78; N, 6.59.

EXAMPLE 30(3-p-chlorophenyl-3,4,5,6-tetrahydro-β-carboline-5-carboxylato)_(2n)-(aqua)_(2n) -copper(II)_(n),[Cu(II)_(n) (cp-tcca)_(2n) (H₂ O)_(2n) ]

The copper coordination compound of the parent acid (5 g, 0.015 mol wasprepared as described for example 1 except3-p-chlorophenyl-3,4,5,6-tetrahydro-β-carboline-5-carboxylic acid wassubstituted for L-tryptophan. An olive drab precipitate was collected byfiltration, washed with 500 ml of H₂ O, 300 ml of diethylether and thenwith acetone until the washings were colorless. This material was driedat 100° C. overnight and 110° C. at 15 mm Hg for 3 hours beforedissolving in acetone and precipitated with Skellysolve B. This material(2 g, 40% yield) was then dried overnight at 60° C. and 15 mm Hg andagain at 125° C. and 15 mm Hg. A sample of this material decomposed overthe range of 205° to 210° C. Analysis Calcd. for C₃₆ H₃₂ Cl₂ N₄ O₆ Cu:C, 57.56; H, 4.30; N, 7.46. Found: C, 57.16; H, 4.15; N, 6.96.

EXAMPLE 31 (3,4,5,6-Tetrahydro-β -carboline-5-carboxylato)_(2n)(aqua)₂.5n -copper(II)_(n),[Cu(II)_(n) (tcca)_(2n) (H₂ O)₂.5n ]

The copper coordination compound of the parent acid (5 g, 0.023 mol) wasprepared as described for example 1 except that3,4,5,6-tetrahydroβ-carboline-5-carboxylic acid was substituted forL-tryptophan. This dark green solid was washed with 500 ml of water,then suspended in 500 ml of boiling acetone and collected by filtration.Drying was done at 100° C. at atmospheric pressure for 24 hours and thenat 110° C. and 15 mm Hg for 3 hours. Subsequent leaching with hotpropylene glycol gave an insoluble material (3.3 g, 52.8% yield) whichrapidly decomposed on heating to 294° C. Analysis Calcd. for C₂₄ H₂₇ N₄O₆.5 Cu: C, 53.47; H, 5.05 and N, 10.40. Found: C, 53.54; H, 4.69 and N,10.58.

EXAMPLE 32 (Hydrocortisone-21-phosphato)_(2n) -(aqua)_(9n)-copper(II)_(3n), [Cu(II)_(3n) (HC-21-phosphate)_(2n) (H₂ O)_(9n) ]

This coordination compound was prepared by dissolving 1 g (0.002 mol) ofthe disodium salt of hydrocortisone-21-phosphate in 25 ml of water andadding this solution dropwise to a stirred solution of cupric acetatemonohydrate, prepared by adding 0.79 g (0.004 mol) of cupric acetatemonohydrate to 25 ml of water. After the addition was complete, stirringwas continued for one-half hour before the light blue precipitate wascollected by filtration and washed with 500 ml of water before airdrying. The yield was 0185 g, 34%. On heating a sample of this materialto 209° C. it decomposed. Analysis Calcd. for C₄₂ H₇₈ O₂₅ P₂ Cu₃ : C,40.82; H, 6.36. Found: C, 40.59; H, 6.18.

EXAMPLE 33 (Hydrocortisone-21-phosphato)_(2n) -(aqua)_(7n)-copper(II)_(3n), [Cu(II)_(3n) (HC-21-phosphate)_(2n) (H₂ O)_(7n])

This coordination compound was prepared by dissolving 1 g (0.002 mol) ofthe disodium salt of hydrocortisone-21 -phosphate in 100 ml of water,adding 1 drop of concentrated hydrochloric acid to give a pH of 6.6 andadding this solution dropwise to a stirred solution of cupric chloridedihydrate (1 g, 0.006 mol) in 50 ml of water. After the addition wascomplete the mixture was allowed to stir for one hour and the light blueprecipitate collected by filtration, washed with 200 ml of water, airdried and weighed (400 mg, 33% yield). A sample of this materialgradually decomposed on heating to 210° C. Analysis Calcd. for C₄₂ H₇₄O₂₃ P₂ Cu₃ : C, 42.05; H, 6.22. Found: C, 42.00; H, 6.21.

EXAMPLE 34 (Hydrocortisone-21-hemisuccinato)_(4n) -(aqua)_(6n) -copper(II)_(2n),[Cu(II)_(2n) (HC-21-hemisuccinate)_(4n) (H₂ O)_(6n) ]

This coordination compound was prepared by dissolving 1 g (0.002 mol) ofhydrocortisone-21-hemisuccinic acid in 250 ml of water with concentratedammonium hydroxide. The resulting pH was 9.0 and was adjusted to pH 7.0with a 10% solution of hydrochloric acid. This solution was then addeddropwise to a stirred solution of cupric chloride dihydrate (1 g, 0.006mol) dissolved in 250 ml of water. The resulting light blue-greenprecipitate was collected, air dried and weighed (1 g, 96% yield). Asample of this material decomposed on heating over the range of 191° to195° C. Analysis Calcd. for C₁₀₀ _(H) ₁₄₄ O₃₈ Cu₂ : C, 57.71; H, 6.97.Found: C, 57.41; H, 7.26.

EXAMPLE 35 (Hydrocortisone-21-hemisuccinato)_(4n) -(aqua)_(7n) -copper(II)₂.5n [Cu(II)₂.5n (HC-21-hemisuccinate)_(2n) (H₂ O)_(7n) ]

This coordination compound was prepared by dissolving 1 g (0.002 mol) ofhydrocortisone-21 -hemisuccinic acid in 20 ml of water with concentratedammonium hydroxide. The resulting pH was 9.5 This solution was thenadded dropwise to a stirred solution of cupric chloride dihydrate (1 g,0.006 mol) dissolved in 15 ml of water. The light blue precipitate whichformed was collected by filtration air dried and weighed (1.2 g, 99%yield). A sample of this material decomposed on heating over the rangeof 196° to 197° C. Analysis Calcd. for C₁₀₀ H₁₆₀ O₄₆ Cu₅ : C, 49.71; H,6.68. Found: C, 49.91; H, 6.63.

EXAMPLE 36 (9 α-Fluoro-11β, 17α,21-trihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione-21-phosphato).sub.2n0(aqua)_(7n) -copper(II)_(3n), [Cu(II)_(3n)(dexamethasone-21-phosphate)_(2n) (H₂ O)_(7n) ]

This coordination compound was prepared by dropping a solution of thedisodium salt of dexamethasone-21-phosphate (9 g, 0.017 mol) dissolvedin 100 ml of water, into a stirred solution of 100 ml of watercontaining 4.6 g (0.003 mol) of cupric chloride dihydrate. After theaddition was completed an additional 300 ml of water was added. Theresulting light blue precipitate was collected by filtration, washedwith water, air dried and weighed (8.1 g, 75% yield). A sample of thismaterial gradually decomposed on heating to 300° C. Analysis Calcd. forC₈₈ H₁₄₀ O₄₆ P₄ F₄ Cu₆ : C, 42.02; H, 5.61. Found: C, 42.04; H, 5.5.

EXAMPLE 37 (9 α-Fluoro-11β,17α-21-trihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione-21-phosphato)_(2n)-(aqua)₁.5n -copper(II)_(3n), [Cu(II)_(3n)(dexamethasone-21-phosphate)_(2n) (H₂ O)₁.5n ]

This coordination compound was prepared by taking 2 g (0.0008 mol) ofthe material prepared in example 36 and suspending it in a stirredmethanol for two hours to remove some of the water of hydration. Afterair drying this material was dried at 45° C. and 15 mm Hg overnight. Asample of this material also decomposed on heating to 300° C. AnalysisCalcd. for C₈₈ H₁₁₈ O₃₅ P₄ F₄ Cu₆ : C, 45.62; H, 5.13. Found: C, 45.51;H, 5.48.

EXAMPLE 38 [1-(p-Chlorobenzoyl)-5-methoxy-2-methylindole-3-acetato]_(4n)-(aqua)_(4n) -copper(II)_(2n),Cu(II)_(2n)[1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate]_(4n) (H₂O)_(4n)

This coordination compound was synthesized from the sodium salt of theparent acid (5 g, 0.014 mol), prepared as in example 1 except1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid was used inplace of L-tryptophan, in 200 of water. The solution of the sodium saltwas dropped into a stirred 300 ml water solution of cupric chloridedihydrate (1.95 g, 0.013 mol). The resultant green precipitate wascollected by filtration, washed with water, air dried and weighed (5.6g, 98% yield). A sample of this material decomposed on heating to 190°C. Analysis Calcd. for C₇₆ H₆₈ O₂₀ N₄ Cl₄ Cu₂ : C, 56.13; H, 4.21; N,3.44. Found: C, 56.00; H, 3.78; N, 3.40.

EXAMPLE 39 [1-(p-Chlorobenzoyl)-5-methoxy-2-methylindole-3-acetato]_(4n)-(acetone)_(2n) -copper(II)_(2n),Cu(II)_(2n)[1-p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate]_(4n) (CH₃COCH₃)_(2n)

This coordination was prepared in a manner similar to that described forexample 38, using twice the amount of parent acid and cupric chloridedihydrate. However, after the green precipitate was collected byfiltration it was leached with 1 liter of acetone and the leachateconcentrated to 500 ml. On standing, additional green crystals formed inthe acetone solution. These were collected by filtration, air dried andweighed (6.9 g, 62% yield). A sample of this material decomposed onheating up to and over the range of 190° to 193° C. Analysis Calcd. forC₈₂ H₇₂ O₁₈ N₄ Cl₄ Cu₂ : C, 58.81; H, 4.79; N, 3.21. Found: C, 58.96; H,4.34; N, 3.35.

EXAMPLE 40 (4-n-Butyl-1,2-diphenyl-3,5-pyrazolidinedione)_(2n)-copper(II)_(n),[Cu(II)_(n)(4-n-butyl-1,2-diphenyl-3,5-pyrazolidinedione)_(2n) ]

A solution of the sodium salt of the parent compound4-n-butyl-1,2-diphenyl-3,5-pyrazolidinedione, (5 g, 0.015 mol) dissolvedin 50 ml of 95% ethanol was diluted with 150 ml of H₂ O. To this stirredsolution was added 2.73 g (0.007 mol) of cupric acetate monohydrate, insmall aliquats. The greenish precipitate which formed was collected byfiltration, dried at 95° C. and 15 mm Hg overnight and weighed (4.5 g,94.5% yield). A sample of this material softened and melted over therange of 65° to 75° C. Analysis Calcd. for C₃₈ H₃₈ N₄ O₄ Cu: C, 67.29;N, 5.65; N, 8.26. Found: C, 67.61; H, 5.43; N, 8.28.

EXAMPLE 41 (17-Hydroxy-3-oxo-17 α-pregn-4,6-diene-21-carboxalato)_(2n)-(aqua)_(2n) -copper(II)_(n),[Cu(II)_(n) (17-hydroxy-3-oxo-17α-pregn-4,6-diene-21-carboxylato)_(2n) (H₂ O)_(2n)

The potassium salt of the parent acid (17-hydroxy-3-oxo-17α-pregn-4,6-diene-21-carboxylic acid) (5 g, 0.013 mol) was dissolved in50 ml of water. This solution was dropped into a stirred solution ofcupric acetate monohydrate, prepared by dissolving 5 g (0.012 mol) in 50ml of water. After the addition was completed the mixture was left tostir for an additional one-half hour before removing the precipitate byfiltration. This precipitate was washed with 500 ml of water before airdrying followed by drying at 30° and 15 mm Hg over the weekend. A 5 g,24% yield was obtained. A sample of this material decomposed on heatingover the range of 168°-169° C. This material was redried at 40° and 15mm Hg before obtaining elemental analysis. Analysis Calcd. for C₈₈ H₁₂₈O₂₂ Cu₂ : C, 64.88; H, 7.67. Found; C, 64.44; H, 7.87.

EXAMPLE 42 Bisdiethyldithiocarbamatocopper(II)[Cu(II)(DDC)₂ ]

Three gms (0.013 mol) of sodium diethyldithiocarbamate was stirred inapproximately 300 ml of deionized distilled water and the solutionfilter to remove an insoluble particulate material. An aqueous solutionof anhydrous Cu(II)Cl₂ was prepared by dissolving 1.13 gms (0.008 mol)in approximately 25 ml of deionized distilled water and filtering. Thefiltrate was dropped into the virogously stirred solution of sodiumdiethyldithiocarbamate. The resulting brown precipitate was filteredwith a scintered glass filter funnel, washed three times with deionizeddistilled water, and air dried while attached to a laboratory vacuumline (approximately 15 mm Hg). A sample of the air dried precipitate(1.9 gm) melted with decomposition over the 194° to 196° C. range.Analysis calculated for C₁₀ H₂₀ N₂ S₄ Cu(H₂ O)₀.75 : C, 32.13; H, 5.76;N, 7.50. Found: C, 31.79; H, 5.40; N, 7.51.

Several of the above described compounds were prepared and tested inaccordance with the following recognized test methods:

1. Acetic acid-induced writhing test as described in Koster et al.,"Acetic Acid for Analgesic Screening", Fed.Proc. 18, 412 (1959),incorporated by reference herein; and

2. Adjuvant-induced arthritic pain as described in: S. KUZNA, et al.,Measurement of Arthritic Pain and Effects of Analgesics in theAdjuvant-Treated Rat, Chem. Pharm. Bull. 23, 1184-1191 (1975);

C. A. WINTER, et al., Analgesic Activity of Diflunisal in Rats withHyperalygesia Induced by Freud's Adjuvant, J. Pharmacol. Exp. Ther. 211,678-685 (1979); and

M. E,. ROSENTHALE, et al., Adjuvant Arthritis: Immuno-PathologicalHyperalgesic Features, Fed. Proced. 41, 2577-2582 (1982),

incorporated by reference herein.

More particularly, the following tests were performed with the followingresults.

Acetic Acid-induced Writhing Test

Groups of 10 ICR male mice (Taisho Pharmaceutical Co. Research Center)were used to study each dose of every compound. Ligands or complexeswere administered orally or subcutaneously in 0.1 ml of vehicle per 10 gof body weight 30 minutes before the intrapertioneal injection of 0.1 mlof 0.7% acetic acid solution per 10 g of body weight. Number of writheswere counted for each mouse during a period of 10 to 20 min after aceticacid injection. Inhibitory percent was calculated by comparison with thenumber of writhes in the non-treated control, vehicle-treated, andacetic acid-injected group. The ED₅₀ value and 95% confidence limitswere calculated from the inhibitory percent by the method of Litchfieldand Wilcoxon.

Adjuvant-induced Arthritic Pain

Groups of 5-6 male Sprague-Dawley rats (Taisho Pharmaceutical Co.Research Center) weighing 140 to 160 g at the time of Mycobacteriumbutyricum (adjuvant, Difco Laboratories, Detroit, Mich.) injection wereused to study each compound. Rats were injected intradermally at thebase of the tail with 0.1 ml of a parafin oil suspension of 0.5 mg ofheat-killed mycobacterium. Fifteen to 19 days later, drugs wereadministered orally or subcutaneously in 0.5 ml of vehicle per 100 g ofbody weight to rats showing the nociceptive reaction, vocalizationfollowing a gentle flexion of the tarsal-tibial joint of the inflamedhind-paw. Vocalization responses were measured every hour for 5 hours.Rats that did not show the vocalization response were regarded aspositive for antinociceptive activity. The ED₅₀ value and 95% confidencelimits were calculated from the positive rate for non-treated controls,vehicle-treated adjuvant arthritic rats, by the method of Litchfield andWilcoxin.

Drug Formulations

All drugs were suspended with 5% gum arabic in saline solution or wettedwith enough propylene glycol to give a final concentration of 4%propylene glycol and the wetted solid suspended in 1.4% polyvinylalcohol in saline.

Results

Of the thee mononuclear complexes, Cu(II)-(anthranilate)₂ and Cu(II)(salicylate)₂ were more effective than their parent ligands whileCu(II)-(3,5-dips)₂ was slightly less effective than its parent ligand asanalgesics in the acetic acid-induced writhing model of pain followingoral administration as a 5% gum arabic suspension in saline (Table I).When these complexes were administered in a mixture of 5% propyleneglycol and 1.4% polyvinyl alcohol in saline (PG-PVA vehicle), Cu(II)(anthranilate)₂ and Cu(II)(salicylate)₂ were again more effective thantheir parent ligands and Cu(II)(3,5-dips)₂ was only as effective as itsparent ligand following oral administration in this pain model. Allthree copper complexes were more effective than their parent ligandsfollowing subcutaneous (s.c.) administration and this route ofadministration was more efficacious than oral administration. Thisincrease in potency ranged from 2- to 10-fold, and all three of thesesquare planar complexes were essentially equipotent ED₅₀ =0.2 mmol/kg.

All three binuclear complexes; Cu(II)₂ (aspirinate)₄, Cu(II)₂(niflumate)₄, and Cu(II)₂ (indomethacin)₄ were more effective than theirparent ligands in the acetic acid-induced writhing pain model followingoral administration in both 5% gum arabic and PG-PVA, and they were mosteffective following administration in PG-PVA (Table II). All three ofthese complexes were also more effective than their parent ligandsfollowing s.c. administration, with ED₅₀ values ranging from 0.02 to0.003 mmol/kg. These data show that these binuclear complexes were 10-to 50-fold more effective than the mononuclear complexes, consistentwith potentially greater complex stability due to steric interference toapproach to the open bonding site on copper by competing ligands andgreater lipophilicity.

Data obtained for the analgesic activity of Cu(II)(chloride)₂ andCu(II)₂ (acetate)₄ (Table II), mononuclear and binuclear complexesrespectively, in the writing model show that these compounds were not aseffective as the more strongly bonded complexes (Tables I and II), withED₅₀ values of only 0.60 and 0.32 mmol/kg respectively. However, Cu(II)₂(acetate)₄ was more effective than anthranilic acid, salicylic acid, andaspirin and Cu(II)(chloride)₂ was more effective than salicylic acid andessentially as effective as anthranilic acid.

Data in Table III compare analgesic activities Cu(II)(anthranilate)₂,Cu(II)(salicylate)₂, and Cu(II)(3,5-dips)₂ with their parent ligand inthe adjuvant-induced pain model. Cu(II)(anthranilate)₂ was lesseffective than its parent ligand following oral administration in 5% gumarabic and, apparently, following oral administration in the PG-PVAvehicle. Cu(II)(salicylate)₂ was more effective than its parent ligandfollowing oral administration in both vehicles, while Cu(II)(3,5-dips)₂was essentially equipotent with its ligand following oral administrationin 5% gum arabic and, apparently, more effective than its parent ligandfollowing oral administration in PG-PVA. Each of these three coppercomplexes was 2- to 4-times as effective as its parent ligand followings.c. administration.

As shown in Table IV, Cu(II)₂ (aspirinate)₄ and Cu(II)₂ (niflumate)₄were more effective than their parent ligand in the adjuvant-inducedpain model following oral administration in 5% gum arabic while allthree binuclear complexes were more effective than their parent ligandfollowing oral administration in the PG-PVA vehicle. In addition, allthree complexes were either as effective or more effective followings.c. administration than they were following oral administration. WithED₅₀ values ranging from 0.06 to 0.002 mmol/kg in this pain model, thesecomplexes appear to be as effective or slightly more effective in thispain model than in the writhing pain model. Both Cu(II)(chloride)₂ andCu(II)₂ (acetate)₄ were devoid of analgesic activity in this pain modelat does which produced statistically significant analgesic effects inthe writhing pain model.

Another matter of interest is the comparison of the analgesic activityof these copper complexes with the activity of morphine. ED₅₀ values formorphine in the writhing and adjuvant arthritis pain models were foundto be 0.002 mmol/kg (Table V), the same value obtained for Cu(II)₂(indomethacin)₄ following oral and s.c. administration in both thewrithing pain model (Table II) and the adjuvant arthritis pain model(Table IV).

To evaluate the time course of analgesia associated with a non-steroidalanti-inflammatory agent and its copper complex, salicylic acid and itscomplex were compared in the adjuvant-arthritis pain model followingoral administration in 5% gum arabic. Data presented in FIG. 1 show thatanalgesic activity increased in a dose-related manner and theCu(II)(salicylate)₂ was 7- to 10-times as effective as salicylic acid.In addition, the analgesic activity of Cu(II)(salicylate)₂ appears to bemore sustained than the analgesic activity of salicylic acid sinceanalgesia associated with salicylic acid treatment began to decline inthe 3 to 4 hr interval following treatment while Cu(II)(salicylate)₂analgesia was maintained or increased throughout the entire 5 hourpost-treatment interval. This sustained analgesic effect may be theresult of slower and prolonged gastric absorption of Cu(II)(salicylate)₂in comparison with salicylic acid due to its greater lipophilicity andreduced solubility in the aqueous vehicle.

As shown in Table VI, copper complexes of amino acids were effectivewhile their ligands were ineffective in the acetic acid-induced painmodel but ineffective in the adjuvant-induced arthritic pain model. Eventhough Cu(II)(L-alaninate)₂, Cu(II)(L-cystinate), and Cu(II)(glycinate)₂were less active than the other copper complexes, includingCu(II)(chloride)₂ and Cu(II)₂ (acetate)₄, the fact that each of thesecomplexes was more active than its parent ligand suggests that thisclass of copper complexes may also be important physiologic modulatorsof nociception.

Table VII shows prolonged duration of analgesic effect for bothCu(II)(DDC)₂ and Cu(II)₂ (Indomethacin)₄ complexes.

Table VIII shows the reduction in Cu(II)(DDC)₂ and Cu(II)₂(Indomethacin)₄ induced analgesia by Naloxone, an opioid antagonist.Naloxone antagonism of analgesic shows that the copper complexes haveopioid-like analgesic activity.

Table IX shows potentiation of opioid analgesia by Cu(II)₂(Indomethacin)₄.

Discussion

It was generally found that analgesic activities of copper complexeswere greater following oral treatment using the PG-PVA suspending systemthan they were with the gum arabic suspending system. A copper complexfirmly bonded to gum arabic, or competition by gum arabic for bondingsites on copper and ligand exchange, may account for reduced activityassociated with gum arabic suspension. Neither propylene glycol norpolyvinyl alcohol has functional groups capable of causing thisinterference.

Subcutaneous administration in PG-PVA nearly always produced greateranalgesic effects than oral administration. This is accounted for asbeing due to more complete absorption following s.c. administration ascompared to uncertain absorption following oral administration. Sincehydrophilicity favors solution in aqueous vehicles and gastricabsorption, parent ligands being more hydrophilic than these coppercomplexes are likely to be absorbed more rapidly even though greaterlipid membrane transport is facilitated by lipophilic character. Inspite of these relative differences in absorbability which wouldfacilitate parent ligand activity, these copper complexes were stillmore effective than their parent ligands.

Dissociation of these copper complexes in the stomach can not be used toaccount for analgesic activities of these complexes since their ligandsand more freely dissociable forms of copper, Cu(II)(chloride)₂ andCu(II)₂ (acetate)₄, have less activity than observed for thesecomplexes. In addition, copper complexes have antisecretory activity anddecrease gastric acidity.

It is phenomenal that the copper complex of acetic acid is effective inpreventing pain in the writhing model since the injection of aceticacid, its ligand, is used to produce pain in this model. In addition,irritant-induced anti-inflammatory and concomitant stress-inducedanalgesic activity can not be used to explain these results since themost likely irritant, Cu(II)(chloride)₂, was the least effectivecompound.

These data are consistent with the notion that non-steroidalanti-inflammatory agents form copper complexes in vivo and support thepossibility that copper complex formation in vivo accounts for theanalgesic activity of these anti-inflammatory agents as well. Theobservation that copper complexes are absorbed and mediate analgesiafollowing tissue distribution suggests physiologic and biochemical rolesfor copper in analgesia.

                                      TABLE I                                     __________________________________________________________________________    Analgesic effects of parent ligands and copper complexes on acetic            acid induced writhing in mice                                                            Oral        Subcutaneous  ED50 (mmol/kg)                           Compound   (mmol/kg).sup.a                                                                     (mmol/kg).sup.b                                                                     (mmol/kg).sup.b                                                                      % Inhibition                                                                         (95% C.L.)                               __________________________________________________________________________    Anthranilic acid                                                                         1.46               18     >1.46                                                     2.19         45**   >2.19                                                           0.27   30     0.64                                                            0.55   36     (0.33-1.23)                                                     1.09   71**                                            Cu(II)(anthranilate).sub.2                                                               0.15               25     0.50                                                0.30               47***  (0.18-1.38)                                         0.60               50**                                                             0.89         50**   >0.89                                                           0.07   30     0.22                                                            0.15   42*    (0.08-0.58)                                                     0.30   57**                                            Salicylic acid                                                                           0.91               29     2.13                                                1.81               33*    (1.19-3.83)                                         3.62               73**                                                             2.17         38*    >2.17                                                           0.54   25     1.02                                                            1.09   52**   (0.65-1.62)                                                     2.17   80***                                           Cu(II)(salicylate).sub.2                                                                 0.30               30     0.65                                                0.59               43*    (0.33-1.27)                                         1.18               69***                                                            0.30         20     1.53                                                      0.59         27     (0.61-3.80)                                               1.18         46*                                                                    0.07   40     0.17                                                            0.15   48*    (0.05-0.39)                                                     0.30   66***                                           3,5-Dips   0.22               44*    0.27                                                0.45               66**   (0.14-0.52)                                         0.90               88***                                                            0.22         19     0.44                                                      0.45         56**   (0.29-0.67)                                               0.90         78***                                                                  0.11   22     0.23                                                            0.23   49*    (0.13-0.30)                                                     0.45   91***                                           Cu(II)(3,5-dips).sub.2                                                                   0.20               35     0.40                                                0.40               48*    (0.17-0.98)                                         0.80               66**                                                             0.20         26     0.43                                                      0.40         56*    (0.20-0.91)                                               0.79         62***                                                                  0.10   27     0.20                                                            0.20   45**   (0.12-0.35)                                                     0.40   74***                                           __________________________________________________________________________     .sup.a administered in 5% gum arabic in saline,                               .sup.b administered in 5% propylene glycol and 1.4% polyvinyl alcohol in      saline for s.c. administration.                                               *p < 0.05,                                                                    **p < 0.01,                                                                   ***p < 0.001 versus vehicle treated group.                               

                                      TABLE II                                    __________________________________________________________________________    Analgesic effects of parent ligands and copper complexes on acetic            acid induced writhing in mice                                                             Oral        Subcutaneous  ED50 (mmol/kg)                          Compound    (mmol/kg).sup.a                                                                     (mmol/kg).sup.b                                                                     (mmol/kg).sup.b                                                                      % Inhibition                                                                         (95% C.L.)                              __________________________________________________________________________    Aspirin     0.56               29     1.30                                                1.11               42*    (0.57-2.95)                                         2.22               66**                                                             0.21         32     0.48                                                      0.42         41*    (0.22-1.04)                                               0.84         67***                                                                  0.28   28     0.52                                                            0.56   57**   (0.28-0.96)                                                     1.11   71***                                          Cu(II).sub.2 (aspirinate).sub.4                                                           0.06               37     >0.24                                               0.12               38*                                                        0.24               33                                                               0.09         32*    0.14                                                      0.18         59**   (0.09-0.25)                                               0.36         80***                                                                  0.03   36     0.04                                                            0.06   59*    (0.03-0.08)                                                     0.24   82***                                          Niflumic acid                                                                             0.18               52**   0.15                                                0.35               65***  (0.05-0.49)                                         0.71               75***                                                            0.13         38*    0.21                                                      0.27         51**   (0.11-0.40)                                               0.53         80***                                                                  0.04   21     0.10                                                            0.09   54**   (0.05-0.19)                                                     0.18   64**                                           Cu(II).sub.2 (niflumate).sub.4                                                            0.04               37**   0.09                                                0.08               48***  (0.03-0.31)                                         0.16               60***                                                            0.06         33*    0.10                                                      0.12         57***  (0.05-0.20)                                               0.24         73***                                                                  0.01   37*    0.02                                                            0.02   48**   (0.01-0.08)                                                     0.04   58***                                          Indomethacin                                                                              0.01               36*    0.04                                                0.03               42**   (0.01-0.13)                                         0.06               58**                                                             0.007        27     0.01                                                      0.014        60**   (0.01-0.03)                                               0.028        68***                                                                  0.007  19     0.02                                                            0.014  36     (0.01-0.04)                                                     0.056  60**                                           Cu(II).sub.2 (indomethacin).sub.4                                                         0.006              33     0.012                                               0.013              50**   (0.005-0.028)                                       0.026              73***                                                            0.001        38     0.002                                                     0.002        53**   (0.001-0.003)                                             0.004        75***                                                                  0.002  34     0.003                                                           0.003  53*    (0.001-0.006)                                                   0.006  70**                                           Cu(II)(chloride).sub.2  0.56   48**   0.60                                                            1.12   69***  (0.30-1.2)                                                      2.24   83***                                          Cu(II).sub.2 (acetate).sub.4                                                                          0.21   42*    0.32                                                            0.41   59***  (0.08-1.30)                                                     0.83   61***                                          __________________________________________________________________________     .sup.a administered in 5% gum arabic in saline,                               .sup.b administered in 5% propylene glycol 1.4% polyvinyl alcohol in          saline for s.c. administration.                                               *p < 0.05,                                                                    **p < 0.01,                                                                   ***p < 0.001 versus vehicle treated group.                               

                                      TABLE III                                   __________________________________________________________________________    Analgesic effects of parent ligands and their copper complexes on             adjuvant-induced arthritic pain in rats.                                                 Oral        Subcutaneous  ED50 (mmol/kg)                           Compound   (mmol/kg).sup.a                                                                     (mmol/kg).sup.b                                                                     (mmol/kg).sup.b                                                                      % Inhibition                                                                         (95% C.L.)                               __________________________________________________________________________    Anthranilic Acid                                                                         0.36               23     0.83                                                0.73               41     (0.43-1.61)                                         1.46               73                                                               1.46         37     >1.46                                    Cu(II)(anthranilate).sub.2                                                               0.30                0     >0.60                                               0.60               10                                                               0.60         17     >0.60                                                           0.07   20     0.19                                                            0.15   43     (0.009-0.42)                                                    0.30   63                                              Saliclylic acid                                                                          1.09               27     2.33                                                2.17               57     (1.13-4.79)                                         4.34               87                                                               0.72         33     1.83                                                      1.44         43     (0.49-6.81)                                               2.88         60                                              Cu(II)(salicylate).sub.2                                                                 0.15               27     0.25                                                0.30               57     (0.13-0.43)                                         0.59               73                                                               0.15         30     0.25                                                      0.30         47     (0.13-0.48)                                               0.59         90                                                                     0.04   20     0.12                                                            0.07   37     (0.05-0.29)                                                     0.15   57                                              3,5-Dips   0.22               30     0.36                                                0.45               53     (0.20-0.66)                                         0.90               92                                                               0.45  27            >0.90                                                     0.90         43                                              Cu(II)(3,5-dips).sub.2                                                                   0.10                7     0.43                                                0.20               20     (0.20-0.93)                                         0.40               47                                                               0.40         40     >0.40                                                           0.05   23     0.12                                                            0.10   37     (0.06-0.25)                                                     0.20   70                                              __________________________________________________________________________     .sup.a administered in 5% gum arabic in saline,                               .sup.b administered in 5% propylene glycol and 1.4% polyvinyl alcohol in      saline for s.c. administration.                                          

                                      TABLE IV                                    __________________________________________________________________________    Analgesic effects of parent ligands and their copper complexes on             adjuvant-induced arthritic pain in rats.                                                  Oral        Subcutaneous  ED50 (mmol/kg)                          Compound    (mmol/kg).sup.a                                                                     (mmol/kg).sup.b                                                                     (mmol/kg).sup.D                                                                      % Inhibition                                                                         (95% C.L.)                              __________________________________________________________________________    Aspirin     0.28               27     0.62                                                0.56               43     (0.32 -1.36)                                        1.11               70                                                               0.56         30     1.41                                                      1.11         40     (0.50 -3.96)                                              2.22         63                                             Cu(II).sub.2 (aspirinate).sub.4                                                           0.06                7     0.29                                                0.12               17     (0.13 -0.65)                                        0.24               43                                                               0.03         13     0.09                                                      0.06         30     (0.04 -0.21)                                              0.12         60                                                                     0.03   23     0.06                                                            0.06   50     (0.03 -0.12)                                                    0.12   73                                             Niflumic acid                                                                             0.18               13     0.42                                                0.35               27     (0.26 -0.68)                                        0.71               87                                                               0.18         23     0.48                                                      0.35         43     (0.19 -1.20)                                              0.71         60                                             Cu(II).sub.2 (niflumate).sub.4                                                            0.04                7     0.18                                                0.08               13     (0.09-0.38)                                         0.16               47                                                               0.16         37     >0.16                                                           0.01   17                                                                     0.02   50     0.03                                                            0.04   60     (0.01-0.06)                             Indomethacin                                                                              0.001              27     0.003                                               0.003              43     (0.001-0.006)                                       0.006              77                                                               0.007        23     0.02                                                      0.014        43     (0.01-0.03)                                               0.028        70                                             Cu(II).sub.2 (indomethacin).sub.4                                                         0.003              27     0.007                                               0.006              47     (0.004-0.15)                                        0.013              70                                                               0.001        20     0.002                                                     0.002        40     (0.001-0.003)                                             0.003        87                                                                     0.001  17     0.002                                                           0.002  43     (0.001-0.005)                                                   0.003  60                                             Cu(II)(chloride).sub.2                                                                          2.24          0     >2.24                                                           2.24    3     >2.24                                   Cu(II).sub.2 (acetate).sub.4                                                                    0.83          0     >0.83                                                           0.83    3     >0.83                                   __________________________________________________________________________     .sup.a administered in 5% gum arabic in saline,                               .sup.b administered in 5% proylene glycol and 1.4% polyvinyl alcohol in       saline for s.c. administration.                                          

                  TABLE V                                                         ______________________________________                                        Analgesic activity of morphine                                                in the acetic acid induced writhing                                           (W) and adjuvant arthritis (AA) pain models.                                                        ED50(mmol/kg)                                           Dose                  (95% of C.L.)                                           (mmol/kg).sup.a                                                                         % Inhibition                                                                              W                 AA                                    ______________________________________                                        0.001     35          0.002                                                   0.002     44*         (0.001-                                                                       0.003)                                                  0.004     89***                                                               0.001     20                                                                  0.002     40                       0.002                                      0.004     60                       (0.001-                                                                       0.005)                                     ______________________________________                                         .sup.a Administered subcutaneously as the hydrochloride salt in saline.  

                  TABLE VI                                                        ______________________________________                                        Analgesic effects of amino acids and their copper complexes on                acetic acid induced writhing in mice and adjuvant-induced                     arthritic pain in rats.                                                                    Oral      %        ED50 (mmol/kg)                                Compound     (mmol/kg).sup.a                                                                         Inhibition                                                                             (95% C.L.)                                    ______________________________________                                        L-alanine    4.49      14       >4.49                                         Cu(II)(L-alaninate).sub.2                                                                  0.42      22        0.92                                                      0.83       48**    (0.54-1.56)                                                1.67       71**                                                               0.42.sup.b                                                                              0        >0.42                                         L-cysteine   3.30      -5       >3.30                                         Cu(II)(L-cystinate)                                                                        0.33       35*     >0.33                                                      0.33.sup.b                                                                              0        >0.33                                         Glycine      5.33       36*     >5.33                                         Cu(II)(glycinate).sub.2                                                                    1.89       48**    >1.89                                         ______________________________________                                         .sup.a administered in 5% gum arabic in saline,                               .sup.b activity in adjuvantinduced arthritic pain.                            *p < 0.05,                                                                    **p < 0.01,                                                                   ***p < 0.01 versus. vehicle treated group.                               

                                      TABLE VII                                   __________________________________________________________________________    Measurement of time of peak activity for Sodium                               Diethyldithiocarbonate (DDC), Cu(II)(DDC).sub.2 and                           Cu(II).sub.2 (indomethacin).sub.4 in the acetic acid-induced                  writhing mouse pain model.                                                                           Inhibition %                                                      Dose        Time after administration (min)                        Compound   (umol/kg)                                                                           Route                                                                             N 30 60 120                                                                              180                                                                              240                                        __________________________________________________________________________    NaDDC      584   s.c.                                                                              10                                                                              48 53*                                                                              20 18                                            Cu(II)(DCC).sub.2                                                                        555   s.c.                                                                              10                                                                              29 42*                                                                               45*                                                                             29                                            Cu(II).sub.2                                                                             2     p.o.                                                                              10                                                                              54**                                                                             49*                                                                              43  68*                                                                             33                                         (indomethacin).sub.4                                                          __________________________________________________________________________     *p 0.05,                                                                      **p 0.01 versus PGPVA saline vehicle treated group (ttest) N: number of       animals.                                                                 

                                      TABLE VIII                                  __________________________________________________________________________    Naloxone reversal of analgesia in the acetic                                  acid-induced writhing mouse pain model.                                                                     ED.sub.50                                                    Dose        %    umol/kg                                         Compound     (umol/kg)                                                                           Route                                                                             N Inhibition                                                                         (95% C.L.)                                      __________________________________________________________________________    Cu(II).sub.2 (DDC).sub.2                                                                   555   s.c.                                                                              10                                                                              45*                                                  Naloxone     555   s.c.                                                                              10                                                                              29                                                   +Cu(II)(DDC).sub.2                                                            Cu(II).sub.2 0.5   p.o.                                                                              10                                                                              43** 0.6                                             (indomethacin).sub.4                                                                       1     p.o.                                                                              10                                                                              62***                                                                              (0.3-1.4)                                                    2     p.o.                                                                              10                                                                              76***                                                Naloxone                                                                      +Cu(II).sub.2                                                                              0.5   p.o.                                                                              10                                                                              19   1.1                                             (indomethacin).sub.4                                                          +Cu(II).sub.2                                                                              1     p.o.                                                                              10                                                                              52***                                                                              (0.6-1.8)                                       (indomethacin).sub.4                                                          +Cu(II).sub.2                                                                              2     p.o.                                                                              10                                                                              69                                                   (indomethacin).sub.4                                                          __________________________________________________________________________     *p 0.05,                                                                      **p 0.01,                                                                     ***p 0.001 versus PGPVA saline vehicle treated group (ttest) N: number of     animals. NaloxoneHCL (3 umol/kg. i.v., in saline, Endo Lab.) was              administered 5 min. before acetic acid injection.                        

                  TABLE IX                                                        ______________________________________                                        Comparison of the analgesic activity of                                       Cu(II).sub.2 (indomethacin).sub.4 and morphine in the acetic                  acid-induced writhing mouse pain model.                                                                             ED.sub.50                                              Dose.sup.a     %       umol/kg                                 Compound       umol/kg  N     Inhibition                                                                            (C.L.)                                  ______________________________________                                        Cu(II).sub.2 (indomethacin).sub.2                                                            0.5      10    21                                                             1.0      10    46*     1.5                                                    2.0      10    54**    (0.7-3.1)                               Morphine HCl   1.0      10    35**    1.6                                                    2.0      10    44**    (1.0-2.5)                                              4.0      10    89****                                          Morphine HCl   1.0      10    50**                                            +Cu(II).sub.2 (indomethacin).sub.4.sup.b                                                     2.0      10    85****  1.0                                     (0.5 umol/kg)  4.0      10    98****  (0.3-1.7)                               ______________________________________                                         *p 0.05 versus PGPVA saline vehicle treated group (ttest).                    **p 0.05 versus saline vehicle treatment group (ttest).                       ***p 0.01 versus saline vehicle treatment group (ttest).                      ****p 0.001 versus saline vehicle treatment group (ttest).                    .sup.a administered orally.                                                   .sup.b administered subcutaneously just before morphine administration.       N: number of animals.                                                    

Having thus described my invention, I claim:
 1. A process for treatinganalgesia in an animal body comprisingadministering enterally orparenterally an effective amount of a copper coordination compound tosaid animal body, said copper coordination compound having the formula##STR1## where R is alkyl, substituted alkyl, alkylmercaptan,alkyldisulfide, alkylester, alkylamine, or hydrogen and R' is amine,aminoalkyl, aromatic substituted aminoalkyl, or hydrogen wherein n and yare numerals and y may equal 2n.
 2. The process of claim 1 wherein theamount administered is about 0.1 to 500 mg. per kilogram of body weight.3. The process of claim 1 wherein the copper coordination compoundis(Hydrocortisone-21-hemisuccinato)_(4n) -(aqua)_(6n)-copper(II)_(2n),[Cu(II_(2n) (HC-21-hemisuccinate)_(4n) (H₂ O)_(6n) ],(hydrocortisone-21-hemisuccinato)_(4n) -(aqua)_(7n) -copper(II)₂.5[Cu(II)₂.5n (HC-21-hemisuccinate)_(2n) (H₂ O)_(7n) ],(17-Hydroxy-3-oxo-17 α-pregn-4,6-diene-21-carboxylateo)_(2n)-(aqua)_(2n) -copper(II)_(n),[Cu(II)_(n) (17-hydroxy-3-oxo-17α-pregn-4,6-diene-21-carboxylato)_(2n) (H₂ O)_(2n) ], and mixturesthereof.